The development of an effective HIV-1 vaccine remains a urgent goal. Efforts to develop a protective HIV-1 vaccine have been hindered by difficulties in identifying epitopes capable of inducing broad neutralizing antibody responses. In fact, the high mutation rate occurring in HIV-1 envelope proteins and the complex structure of gp120 as an oligomer associated with gp41 result in a high degree of antigenic polymorphism. Furthermore, a vaccine formulation should take into account the subtype prevalence in different geographic regions as well as the insurgence of new HIV isolates. To overcome these obstacles, we screened Random Peptide Libraries (RPL) using sera from HIV-infected subjects in order to identify antigenic and immunogenic mimics of HIV-1 epitopes. After extensive counter-screening with HIV- negative sera, we isolated peptides specifically recognized by antibodies from HIV-1 infected individuals. These peptides behaved as antigenic mimics of linear or conformational HIV-1 or SHIV epitopes generated in vivo in the course of natural infection. The selected epitopes were immunogenic in mice, where they elicited HIV-specific antibodies that effectively neutralized HIV-1 isolates (G. Scala et al., The Journal of Immunology, 1999, 162:6155). Based on this experience, we propose to select pools of immunogenic HIV-1 mimotopes by taking advantage of the HIV-specific antibody repertoire induced by the natural infection. The study should help in developing an effective HIV-1 vaccine. - HIV-1; epitopes; vaccine; random peptide libraries - Human Subjects